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To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bers DM. Am J Physiol Cell Physiol 281: C2049-C2060, 2001). We incorporated equations for Ca2+ and Mg2+ buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive K+ channel and L-type Ca2+ channel, Na+-K+-ATPase, and sarcolemmal and sarcoplasmic Ca2+-ATPases, and equations describing the basic pathways (creatine and adenylate kinase reactions) known to communicate the flux changes generated by intracellular ATPases. Under normal conditions and during 20 mm of ischemia, the three regions were characterized by different INa, Ito, IKr, IKs, and IKp channel properties. The results indicate that the ATP-sensitive K+ channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, Pi, total Mg2+, Na+, K+, Ca2+, and pH diastolic levels are normal. The model predicts that only KATP ionophore (Kir6.2 subunit) and not the regulatory subunit (SUR2A) might differ from endocardium to epicardium. The analysis suggests that during ischemia, the inhomogeneous accumulation of the metabolites in the tissue sublayers may alter in a very irregular manner the KATP channel opening through metabolic interactions with the endogenous PI cascade (PIP2, PIP) that in turn may cause differential action potential shortening among the ventricular myocyte subtypes. The model predictions are in qualitative agreement with experimental data measured under normal and ischemic conditions in rabbit ventricular myocytes. [ABSTRACT FROM AUTHOR]

The β-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating β-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of β[sub 1]-adrenergic receptor, and manipulating the affinity of G[sub s]α for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6× increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the β-adrenergic signaling network may be understood within the context of integrative cellular physiology. [ABSTRACT FROM AUTHOR]

Little is known about how small variations in ionic currents and Ca2+ and Na+ diffusion coefficients impact action potential and Ca2+ dynamics in rabbit ventricular myocytes. We applied sensitivity analysis to quantify the sensitivity of Shannon et al. model (Biophys. J., 2004) to 5%-10% changes in currents conductance, channels distribution, and ion diffusion in rabbit ventricular cells. We found that action potential duration and Ca2+ peaks are highly sensitive to 10% increase in L-type Ca2+ current; moderately influenced by 10% increase in Na+-Ca2+ exchanger, Na+-K+ pump, rapid delayed and slow transient outward K+ currents, and Cl-background current; insensitive to 10% increases in all other ionic currents and sarcoplasmic reticulum Ca2+ fluxes. Cell electrical activity is strongly affected by 5% shift of L-type Ca2+ channels and Na+-Ca2+ exchanger in between junctional and submembrane spaces while Ca2+-activated Cl--channel redistribution has the modest effect. Small changes in submembrane and cytosolic diffusion coefficients for Ca2+, but not in Na+ transfer, may alter notably myocyte contraction. Our studies highlight the need for more precise measurements and further extending and testing of the Shannon et al. model. Our results demonstrate usefulness of sensitivity analysis to identify specific knowledge gaps and controversies related to ventricular cell electrophysiology and Ca2+ signaling. [ABSTRACT FROM AUTHOR]

Abstract: Intercellular calcium waves in cardiac myocytes are a well-recognized, if incompletely understood, phenomenon. In a variety of preparations, investigators have reported multi-cellular calcium waves or triggered propagated contractions, but the mechanisms of propagation and pathological importance of these events remain unclear. Here, we review existing experimental data and present a computational approach to investigate the mechanisms of multi-cellular calcium wave propagation. Over the past 50 years, the standard modeling paradigm for excitable cardiac tissue has seen increasingly detailed models of the dynamics of individual cells coupled in tissue solely by intercellular and interstitial current flow. Although very successful, this modeling regime has been unable to capture two important phenomena: 1) the slow intercellular calcium waves observed experimentally, and 2) how intercellular calcium events resulting in delayed after depolarizations at the cellular level could overcome a source-sink mismatch to initiate depolarization waves in tissue. In this paper, we introduce a mathematical model with subcellular spatial resolution, in which we allow both inter- and intracellular current flow and calcium diffusion. In simulations of coupled cells employing this model, we observe: a) slow inter-cellular calcium waves propagating at about 0.1 mm/s, b) faster Calcium-Depolarization-Calcium (CDC) waves, traveling at about 1 mm/s, and c) CDC-waves that can set off fast depolarization-waves (50 cm/s) in tissue with varying gap-junction conductivity. [Copyright &y& Elsevier]

Key points We have developed a detailed computational model of a cardiac Ca2+ spark based on a three dimensional reconstruction of electron tomograms., Our model predicts near total junctional Ca2+ depletion after the spark, while regional Ca2+ reserve is preserved. The local Ca2+ gradient inferred by these findings reconciles previous model predictions with experimental measurements., Differences in local distribution of calsequestrin have a profound impact on spark termination time, as reported by Fluo5, solely based on its Ca2+ buffering capacity., The SERCA pump can prolong spark release time by pumping Ca2+ back into the junctional SR during the spark., Abstract Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca2+ release unit (CRU) is the fundamental event of cardiac excitation-contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca2+ leak in cardiomyocytes. Previous model studies have predicted that the duration and magnitude of the spark is determined by the local CRU geometry, as well as the localization and density of Ca2+ handling proteins. We have created a detailed computational model of a CRU, and developed novel tools to generate the computational geometry from electron tomographic images. Ca2+ diffusion was modelled within the SR and the cytosol to examine the effects of localization and density of the Na+/Ca2+ exchanger, sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA), and calsequestrin on spark dynamics. We reconcile previous model predictions of approximately 90% local Ca2+ depletion in junctional SR, with experimental reports of about 40%. This analysis supports the hypothesis that dye kinetics and optical averaging effects can have a significant impact on measures of spark dynamics. Our model also predicts that distributing calsequestrin within non-junctional Z-disc SR compartments, in addition to the junctional compartment, prolongs spark release time as reported by Fluo5. By pumping Ca2+ back into the SR during a release, SERCA is able to prolong a Ca2+ spark, and this may contribute to SERCA-dependent changes in Ca2+ wave speed. Finally, we show that including the Na+/Ca2+ exchanger inside the dyadic cleft does not alter local [Ca2+] during a spark. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various papers within the issue on topics including biomedical engineering, computational biology and the role of ontologies in biology.

Spatial-temporal Ca^2+ dynamics due to Ca^2+ release, buffering, and reuptaking plays a central role in studying excitation–contraction (E–C) coupling in both normal and diseased cardiac myocytes. In this paper, we employ two numerical methods, namely, the meshless method and the finite element method, to model such Ca^2+ behaviors by solving a nonlinear system of reaction–diffusion partial differential equations at two scales. In particular, a subcellular model containing several realistic transverse tubules (or t-tubules) is investigated and assumed to reside at different locations relative to the cell membrane. To this end, the Ca^2+ concentration calculated from the whole-cell modeling is adopted as part of the boundary constraint in the subcellular model. The preliminary simulations show that Ca^2+ concentration changes in ventricular myocytes are mainly influenced by calcium release from t-tubules. [ABSTRACT FROM AUTHOR]

The t-tubule's of mammalian ventricular myocytes are invaginations of the cell membrane that occur at each Z-line. These invaginations branch within the cell to form a complex network that allows rapid propagation of the electrical signal, and hence synchronous rise of intracellular calcium (Ca2+). To investigate how the t-tubulemicroanatomy and the distribution of membrane Ca2+ flux affect cardiac excitation-contraction coupling we developed a 3-D continuum model of Ca2+ signaling, buffering and diffusion in rat ventricular myocytes. The transverse-axial t-tubule geometry was derived from light microscopy structural data. To solve the nonlinear reaction-diffusion system we extended SMOL software tool (http://mccammon.ucsd.edu/smol/). The analysis suggests that the quantitative understanding of the Ca2+ signaling requires more accurate knowledge of the t-tubule ultra-structure and Ca2+ flux distribution along the sarcolemma. The results reveal the important role for mobile and stationary Ca2+ buffers, including the Ca2+ indicator dye. In agreement with experiment, in the presence of fluorescence dye and inhibited sarcoplasmic reticulum, the lack of detectible differences in the depolarization-evoked Ca2+ transients was found when the Ca2+ flux was heterogeneously distributed along the sarcolemma. In the absence of fluorescence dye, strongly non-uniform Ca2+ signals are predicted. Even at modest elevation of Ca2+, reached during Ca2+ influx, large and steep Ca2+ gradients are found in the narrow sub-sarcolemmal space. The model predicts that the branched t-tubule structure and changes in the normal Ca2+ flux density along the cell membrane support initiation and propagation of Ca2+ waves in rat myocytes. [ABSTRACT FROM AUTHOR]